Aicardi–Goutières syndrome

Not to be confused with Aicardi syndrome.

Aicardi–Goutières Syndrome (AGS) is a rare, inherited neurodevelopmental disorder that primarily affects the brain, immune system, and skin. Initially described by Jean Aicardi and Françoise Goutières in 1984, AGS often mimics congenital viral infections and presents with a spectrum of clinical manifestations.

Clinical Features

AGS typically manifests in early infancy, although later-onset cases have been reported. The clinical presentation includes:

• Neurological Symptoms:
• Encephalopathy: Characterized by irritability, persistent crying, and feeding difficulties.
• Developmental Regression: Loss of previously acquired motor and cognitive skills.
• Microcephaly: Reduced head circumference due to impaired brain growth.
• Spasticity and Dystonia: Increased muscle tone and involuntary muscle contractions leading to movement abnormalities.
• Seizures: Occur in some individuals, varying in severity.

• Dermatological Features:
• Chilblain Lesions: Painful, red or purple skin lesions typically found on fingers, toes, and ears, exacerbated by cold exposure.

• Other Manifestations:
• Hepatosplenomegaly: Enlargement of the liver and spleen.
• Thrombocytopenia: Low platelet count, leading to increased bleeding risk.
• Glaucoma: Elevated intraocular pressure, potentially resulting in vision loss.

Pathophysiology

AGS is associated with mutations in several genes involved in nucleic acid metabolism and the innate immune response. These genetic alterations lead to the accumulation of nucleic acids, triggering an inappropriate activation of the immune system, particularly the type I interferon pathway. This aberrant immune response results in inflammation and subsequent damage to neural tissues.

Genetics

AGS exhibits genetic heterogeneity with both autosomal recessive and autosomal dominant inheritance patterns. The following genes have been implicated:

• TREX1: Encodes a 3' repair exonuclease; mutations are linked to severe early-onset AGS.
• RNASEH2A, RNASEH2B, RNASEH2C: Encode subunits of the ribonuclease H2 complex; mutations are the most common cause of AGS.
• SAMHD1: Encodes a deoxynucleoside triphosphate triphosphohydrolase; mutations can lead to variable disease severity.
• ADAR: Encodes an adenosine deaminase acting on RNA; mutations are associated with neurological manifestations.
• IFIH1: Encodes a cytosolic double-stranded RNA receptor; gain-of-function mutations can cause AGS.

Diagnosis

The diagnosis of AGS is based on clinical evaluation, neuroimaging findings, laboratory tests, and genetic analysis.

• Neuroimaging:
• Cranial CT scans: Reveal bilateral basal ganglia calcifications.
• MRI: Shows white matter abnormalities, cerebral atrophy, and, in some cases, cystic changes.

• Laboratory Findings:
• Cerebrospinal Fluid (CSF): Lymphocytosis and elevated interferon-alpha levels.
• Blood Tests: Elevated liver enzymes and thrombocytopenia.

• Genetic Testing: Identifies pathogenic mutations in the associated genes, confirming the diagnosis.

Management

Currently, there is no cure for AGS; treatment is primarily supportive and symptomatic:

• Neurological Care:
• Antiepileptic Drugs: Manage seizures.
• Physical and Occupational Therapy: Improve motor function and prevent contractures.

• Dermatological Care:
• Protective Measures: Prevent chilblain lesions by avoiding cold exposure and using appropriate clothing.

• Ophthalmologic Care:
• Regular Eye Examinations: Early detection and management of glaucoma.

• Immunomodulatory Therapies: Research is ongoing to evaluate their efficacy in AGS.

Prognosis

The prognosis of AGS varies widely, depending on the specific genetic mutation and severity of symptoms. While some individuals experience severe neurological impairment and early mortality, others may have milder forms of the disease with longer survival. Early intervention and multidisciplinary care are essential to optimize outcomes.

See Also

• Leukodystrophy
• Encephalopathy
• Autoimmune diseases
• Interferonopathies

External Links

• National Institute of Neurological Disorders and Stroke - Aicardi-Goutières Syndrome
• MedlinePlus Genetics - Aicardi-Goutières Syndrome
• National Organization for Rare Disorders - Aicardi-Goutières Syndrome
• Orphanet - Aicardi-Goutières Syndrome

Classification	ICD-10: G31.8 OMIM: 225750 DiseasesDB: 31680
External resources	Orphanet: 51

NIH genetic and rare disease info

• NIH info on Aicardi–Goutières syndrome

Aicardi–Goutières syndrome is a rare disease.